Rita G. Hazell

Catalytic Enantioselective Aza-Diels-Alder Reactions of Imines-An Approach to Optically Active Nonproteinogenicα-Amino Acids

A catalytic enantioselective aza-Diels-Alder reaction of imines has been developed. The reaction of N-tosyl alpha-imino ester with different dienes including activated, non-activated, cyclic, and acyclic dienes has been investigated in the presence of various chiral Lewis acids. A series of phosphino-oxazoline ligands have been synthesized and evaluated for the reaction. It was found that the combination of phosphino-oxazoline ligands with copper(I) salts gives the best results for the activated dienes, while BINAP-copper(I) complexes are good catalysts for all the dienes studied. In the case of activated acyclic dienes the aza-Diels-Alder products can be obtained in higher than 80% isolated yield and 96% ee, while for the unactivated cyclic dienes the exo diastereomer is formed as the major product in up to 95 % ee. For an activated cyclic conjugated diene, 2-trimethylsilyloxy-1,3-cyclohexadiene, the reaction proceeds as a Mannich-type addition reaction giving optically active gamma-oxo alpha-amino acid derivatives in good yields and up to 96% ee. The reaction of an unactivated acyclic diene, 2,3-dimethyl-1,3-butadiene, with the N-tosyl alpha-imino ester gives both the aza-Diels-Alder and aza-ene products, in a ratio of 9:1 favoring the aza-Diels-Alder product. Furthermore, a series of different imines have been synthesized and investigated as possible substrates for the present catalytic enantioselective aza-Diels-Alder reaction in order to obtain mechanistic insight. All imines studied gave moderate to high ee. Particularly, the reaction of the N-phenyl and N-p-methoxyphenyl substituted glyoxylate imines with Danishefskys diene proceeded well affording the corresponding aza-Diels-Alder product in high yield with up to 91% ee at room temperature. The present catalytic enantioselective reaction of imines provided an effective route to optically active nonproteinogenic alpha-amino acids. The products of the catalytic enantioselective aza-Diels-Alder reaction of the cyclic dienes can be used for the preparation of key compounds such as natural products and compounds of pharmaceutical interest. The absolute configurations of five products have been solved by X-ray structural analysis, and it is found that the absolute configuration of the aza-Diels-Alder adduct is dependent on the substituent on the imine nitrogen atom. It turned out that the N-tosyl glyoxylate imine and N-p-methoxyphenyl glyoxylate imine give the aza-Diels-Alder adduct with opposite absolute configuration using the same enantiomer of the catalyst. On the basis of the results the mechanistic aspects for the reactions are discussed.

On the Intermediates in Chiral Bis(oxazoline)copper(II)‐Catalyzed Enantioselective Reactions—Experimental and Theoretical Investigations

The intermediates in the chiral bis(oxazoline)copper(II)-catalyzed reactions have been investigated by means of experimental and theoretical investigations. It is shown that the absolute configuration of the hetero-Diels-Alder adduct obtained from the reaction of ethyl glyoxylate with 1,3-cyclohexadiene in the presence of the chiral bis(phenyloxazoline)copper(II) is dependent on the solvent. In this case, a linear relationship between the enantiomeric excess (ee) and the dielectric constant of the solvent was observed. However, the enantiomeric excess for the adduct obtained with the chiral bis(tert-butyloxazoline)copper(II) complex is independent of the solvent. The addition of different coordinating solvents to the chiral catalysts was investigated and no effect on the enantioselectivity of the reaction was observed. A series of chiral bis(tert-butyloxazoline)-, bis(phenyloxazoline)-, and bis(indaneoxazoline)copper(II) complexes has been prepared and characterized by X-ray analysis, and the similarity between the structures is discussed. For comparison, two related chiral bis(tert-butyloxazoline)- and bis(phenyloxazoline)zinc(II) complexes were also prepared and characterized. A series of chiral bis(oxazoline)copper(II)-substrate (the substrate being glyoxal or methyl glyoxylate) complexes was investigated by means of ab initio calculations. Calculation of the total energy of the optimized structure of 17-, 19-, and 21-electron bis(oxazoline)copper(II)-substrate complexes give the 17-electron complex as the most stable and the most reactive complex, while the 21-electron complex is less stable and also much less reactive. The optimized structures of both the 17-electron bis(tert-butyloxazoline)- and bis(phenyloxazoline)copper(II)-substrate complexes show that the plane of the substrate molecule is twisted by approximately 40-45 degrees out of the bis(oxazoline)copper(II) plane, in agreement with the X-ray structures. On the basis of the experimental results, X-ray structures, and ab initio calculations, the structure of the intermediate(s) and reactivity of the chiral bis(oxazoline)copper(II)-substrate complexes are discussed.

Enantiospecific synthesis of 1-azafagomine.

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.

Silyl nitronates and nitrile oxides in organic synthesis. A novel route to d,l-deoxysugars. Use of aluminum oxide as solid phase base for generation of

Abstract Novel methodology is developed for a three step synthesis of deoxyaldoses and deoxyketoses: 1. Regioselective addition of silyl nitronate or nitrile oxide to a diene. 2. Stereospecific hydroxylation of the double bond. 3. Unmasking of the aldol moiety by catalytic reduction of the 2-isoxazoline. The syntheses of D,L-deoxyribose, D,L-oleose, D,L-digitoxose, D,L-2-deoxygalactose, 1,3-dideoxyfructose, 3-deoxyfructose etc. are described. Basic aluminum oxide is introduced as a solid phase base for the one step synthesis of 2-isoxazolines from aldoximes and olefins. An X-ray diffraction study of compound 13c verifies the stereochemical assignments.

Indole alkaloids and terpenoids from Tabernaemontana markgrafiana

Abstract The bark of Tabernaemontana markgrafiana yielded five acetylated pentacyclic triterpenes and 24 monoterpene indole alkaloids. The major triterpene

Radical addition of nitrones to acrylates mediated by SmI2: asymmetric synthesis of γ-amino acids employing carbohydrate-based chiral auxiliaries

Alkyl nitrones possessing N-substituted sugars as chiral auxiliaries were found to effectively undergo an SmI(2)-mediated radical addition to n-butyl acrylate affording gamma-amino acid derivatives with high diastereomeric control.

Synthesis, structure, and reactions of thiocarbonic acid derivatives new pentathiodipercarbonates, (RSS)2 CS, α,α,α-tris(disulfides), and the first α,α,α-tris(trisulfide)

Abstract Novel bis(perhaloalkyl) pentathiodipercarbonates 5b-d have been synthesized by reaction of sulfenyl chlorides with metal trithiocarbonates, and the heptathio analog 21a was prepared similarly. Lenthionine 19 is the main product when diiodomethane is treated with sodium tetrathiopercarbonate. A rearrangement of bis(alkyldithio)chloromethanesulfenyl chlorides 22 to alkyldithio) (alkyltrithio)dichloromethanes 24 has been observed. Additions of sulfenyl chlorides and of thiosulfenyl chlorides to the thiocarbonyl compounds 5 and 21a were achieved in acetonitrile. The structures of the first crystalline pentathiodipercarbonate 5a and α,α,α-tris(disulfide) 29a , and of the first reported α,α,α-tris(trisulfide) 31a have been determined by X-ray crystallography.

Catalytic enantioselective formation of aziridines from α-imino esters

A new catalytic enantioselective aziridination reaction of α-imino esters with diazo compounds catalyzed by chiral Lewis acid complexes is presented. A series of N-substituted α-imino esters has been tested as substrates for the aziridination reaction using trimethylsilyldiazomethane as the carbenoid fragment donor catalyzed by various chiral complexes. Both chiral BINAP and bisoxazoline† ligands, in combination with copper(I) salts in particular can catalyze the aziridination reaction leading to the cis-aziridine with up to 72% ee applying BINAP–copper(I) complexes as the catalyst, while the bisoxazoline–copper(I) catalysts give an aziridination reaction with lower diastereoselectivity, however, the trans-aziridine was formed in 69% ee. The influence of diazo compounds, Lewis acids, chiral ligands, solvents and counterion on the reaction course has been investigated and a mechanism for the reaction is discussed in which the α-imino ester coordinates to the chiral catalyst. For trimethylsilyldiazomethane, nucleophilic attack on the coordinated α-imino ester probably takes place in the case of copper(I) as the Lewis acid, while for ethyl diazoacetate the reaction course is dependent on the Lewis acid; for silver(I) a nucleophilic attack is probably also operating, while a metal–carbene intermediate is involved when copper(I) is used.

Catalytic enantioselective addition of aromatic amines to enones: synthesis of optically active β-amino acid derivatives

A catalytic enantioselective addition of aromatic amines to enones has been developed; the potential of the reaction is shown for aromatic amines reacting with alkyl oxazolidinones in good yield and with moderate to excellent enantiomeric excess, and the transformation of the products to β-amino acid amides.

Solid and solution state structures of mono- and di-nuclear iron(III) complexes of related hexadentate and pentadentate aminopyridyl ligands

Two mononuclear iron(III) complexes formed with the related ligands N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (tpen) and N-benzyl-N,N′,N′-tris(2-pyridylmethyl)ethylenediamine (bztpen) have been studied. X-Ray crystallography reveals for the complex [Fe(tpen)][ClO4]3 that tpen acts as a hexadentate ligand in the solid state. In methanol or water containing solutions it was shown by EPR and UV-Vis spectroscopy that one pyridyl arm is exchanged by a solvent molecule. In dmf solution only partial exchange of a pyridyl arm was observed. The complex with the related pentadentate ligand bztpen [Fe(bztpen)Cl][ClO4]2 showed exchange of the coordinated chloride with methanol and water, but not with dmf. In water containing solutions both complexes are slowly converted into the dimeric μ-oxo complexes [(tpen)FeIII(Cl)OFeIII(Cl)(tpen)]2+ or [(bztpen)FeIII(Cl)OFeIII(Cl)(bztpen)]2+. This reaction is accelerated by addition of an excess of chloride.